PROJECT SUMMARY/ABSTRACT Glycemic control strongly predicts outcomes in type 1 diabetes (T1D), yet many children with T1D fail to achieve glycemic targets. This problem is magnified by rising T1D incidence and incomplete understanding of the etiology of T1D. Winter predominance of T1D onset, worsening of glycemic control, and loss of residual beta cell function suggest that there may be shared seasonal triggers that contribute to T1D pathogenesis. Epidemiologic studies using 3-month average glycemic control measures (i.e. glycated hemoglobin) obscure temporal trends. Investigators of potential viral triggers have examined the role of prespecified viruses, but have not conducted comprehensive testing for all human viruses. Wide use of continuous glucose monitoring (CGM) and the availability of systematic tests for all prior viral exposures can now be leveraged to dissect the causes of T1D and highlight relevant biology for T1D prevention and management. Dr. Christina Mills Astley, a pediatric endocrinologist and epidemiologist, will approach seasonality of incident and prevalent T1D using an innovative combination of translational phenotyping, time-series analyses, and integration of external datasets in her Mentored Patient-Oriented Research Career Development Award. She now seeks to build on her prior research experiences in infectious diseases modeling and causal inference for complex data, while acquiring new skills in time-series analysis and bioinformatics, and developing expertise in T1D pathophysiology, including the role of immune dysregulation, inflammation, and metabolic stress. Combined with the high-quality mentorship and supportive environment at Boston Children?s Hospital, these tools will broaden her expertise and enable her to establish an independent research program. In Aim 1, Dr. Astley will use pediatric T1D CGM data and time-series methods (e.g. change point, autoregression, temporal clustering) to define seasonal patterns, both acute and chronic, in clinically-relevant CGM-based glycemic control measures (e.g. coefficient of variation, time in range). In Aim 2, she will quantify the effect of individual, social, and environmental exposures on these glycemic control measures. Finally, in Aim 3, Dr. Astley will apply comprehensive antibody profiling (VirScan) to test which viral infection(s) drive T1D onset, end of remission, and seasonal dysglycemia. Together the results of these investigations will form the basis of a data-driven approach to understand seasonality in T1D, which in turn may be used to recognize optimal timing for anticipatory guidance to mitigate the risk of seasonal hyperglycemia and hypoglycemia, and to identify potential targets for intervention to slow the progression of T1D. Dr. Astley seeks to become an independent physician-scientist with unique expertise in computational epidemiology, translational methodologies, and T1D pathogenesis, so as to improve prevention and treatment. This K23 award will afford her the mentorship, training, expertise, and research to achieve these goals.